There are many steroidal drugs suitable for treating particular responsive dermatological disorders. They have a broad range of applicable biological activities (e.g. cell membrane stabilization, vasoconstrictor activity, anti-mitotic effect, suppression of DNA and protein synthesis, etc.). However, steroids often exhibit undesired local and systemic side effects when used for prolonged periods. These may be manifested in the form of local skin atrophy, or in adrenal atrophy in the most severe case. Furthermore, a reduction in host defense mechanisms to infection may accompany their use.
Beyond the potential undesired side effects, steroids do not interact with the complete biological spectrum of inflammation. For example, ultraviolet (UV) light induced erythema is not amenable to treatment by steroidal anti-inflammatories. UV-induced early changes in skin such as vasodilation are related to the conversion of arachidonic acid to E prostaglandins or to intermediate forms such as HETE (12L-hydroxy-5,8,10,14-eicosatetraenoic acid) or the endoperoxides which are vasoactive and are believed to have cutaneous activity, such as triggering hyperproliferative epidermal activity. See, for example, Bem, J. L. and Greaves, M. W. 1974 Prostaglandin E.sub.1 effects on epidermal cell growth "in vitro." Arch. Derm. Forsch. 251:35-41; Snyder, D. S. and Eaglstein, W. H. 1974 Topical indomethacin and sunburn. Brit. J. Derm. 90:91-93; Snyder, D. S. and Eaglstein, W. H. 1974 Intradermal anti-prostaglandin agents and sunburn. J. Invest. Derm. 62.47-50; and Goldyne, M. E. et al. 1973 Prostaglandin activity in human cutaneous inflammation: Detection by radio-immunoassay. Prostaglandins 4:737-749. See also Hsia, S. L., Ziboh, V. A. and Snyder, D. S. 1974. Naturally occurring and synthetic inhibitors of prostaglandin synthetase of the skin. Prostaglandin Synthetase Inhibitors 353-361. Although it is not understood completely, it is thought that these effects related to prostaglandin biosynthesis are important components of many dermatopathologies, so a drug which will interfere with this biosynthesis should be useful in the clinical improvement of the disease.
There are many non-steroidal compounds or agents which also have anti-inflammatory effects. Many of these are believed to act by blocking the prostaglandin synthetase complex of enzymes that are present in normal skin and are necessary for the biosynthetic processes described above. Furthermore, as a general rule, these drugs are relatively free of unwanted side effects. Examples of such non-steroidal anti-inflammatory compounds include aspirin, indomethacin, suprofen, cliprofen and ethyl 5-p-chlorobenzoyl-1, 4-dimethylpyrrole-2-acetate. While many acylaminophenols, including the compounds employed in the treatment of the present invention, have been reported in the literature and used for a variety of purposes, to our knowledge, none have heretofore been reported to be useful as topical anti-inflammatory agents. A review of Chemical Abstracts has revealed the following disclosures relevant to pharmaceutical activities of related aminophenols as well as pharmaceutical and nonpharmaceutical activities of the substituted aminophenols specified below as being useful in the topical compositions and methods of the present invention. CA 57 16492 (1962) contains a report of anti-rheumatic activity for N-nicotinyl-p-aminophenol and N-succinyl-p-aminophenol, and refers to Austrian Pat. No. 222,647 (1962). p-Aminophenol amides of sperm head oil acids and sperm blubber oil acids, mentioned in Netherlands patent application No. 6,505,431 as having hypocholesterolemic activity, are reported at CA 64 14137 (1966). U.S. Pat. No. 3,081,321 is reported at CA 60 2833 (1964) to disclose analgesic activity of p-aminophenol amides of aliphatic monocarboxylic acids. Analgesic, anti-pyretic and anti-inflammatory activities are attributed to the dipropyl acetyl amide of p-aminophenol at CA 76 153384x (1972), which refers to French M 7624 to Laboratories J. Berthier (1970); and the same activities are reported for the cystein derivative of p-aminophenol at CA 86 107003f (1977), an abstract of an article by Portelli, Renzi, Cervato & Frigeni, Farmaco, Ed. Sci. 31 (11) 767-775 (1976). According to CA 86 43215s (1977), Belgian Pat. No. 834,304 reports that aryl amides of omega-aminoalkanoic acids, having the formula ##STR1## wherein n is 4, 5, 6 or 8, inhibit blood platelet aggregation. CA 89 108193s (1978) has the same report with reference to British Pat. No. 1,498,996, apparently a counterpart of the above Belgian patent. CA 88 58568z (1978) reports that a Japanese patent publication (Kokai No. 77,110,835) discloses that certain benzanilide derivatives (none of which are 4-acylaminophenols, however) have shown anti-inflammatory activity when administered to mice orally or injected i.p.
Salicylaminophenol, which has the structure: ##STR2## [also named 4'-hydroxysalicylanilide; N-(p-hydroxyphenyl) salicylamide, and N-salicoylaminophenol], has been reported to have choleretic activity (Merck Index, Ninth Edition, 6724, page 894); fungistatic activity in vitro [CA 71 69577b, (1969)]; activity in inhibiting allergic reaction or inflammation in mice when administered orally or i.p. [CA 88 58568z, (1978)]; molluscocidal and cercaricidal activity [CA 89 192405t, (1978)]; a photosensitizing effect in guinea pigs [CA 83 37501d, (1975)]; anthelminthic activity [CA 80 133081a, (1974)]and utility as an antioxidant for unsaturated rubber [CA 91 6227e, (1979)].
For the acylaminophenols used in the composition and treatment of the present invention, having the formula: ##STR3## wherein n is an integer from 5 to 11, inclusive and closely related structural analogs (wherein n is less than 5 or greater than 11) the following activities have been reported:
n=2 analgesic [CA 74 123508g, (1971)]; PA1 n=2 or 3 anti-inflammatory, antiedemic, analgesic, antipyretic and sedative--when combined with the enzymes, muramidase and amylase [CA 71 42305z (1969)--refers to French Pat. No. M 5,575]; PA1 n=3 increases biodegradability of polyolefins [CA 83 194578b, (1975)--refers to U.S. Pat. No. 3,903,029]; stabilizer for methyl methacrylate polymers [CA 77 140970f (1972)--refers to Japan Pat. No. 72 07 629], PA1 n=7 local anesthetic [CA 50 9424 refers to Bull. Soc. Chim. France (1955) 1603-9]; PA1 n=8,11 polyester stablizer [CA 76 154779s (1972) refers to Ger. Offen. No. 2,036,712]; PA1 n=3,8,11 polyacetal stabilizer [CA 66 29609d (1967)--refers to U.S. Pat. No. 3,288,885]; PA1 n=9 desensitizes thermoregulatory reflexes in guinea pigs [CA 72 76596f (1970)--refers to J. Physiol. (London) 206 (3) 495.varies.507(1970)]; PA1 n=11 thermal stabilizer in resins [CA 86 107522z (1977)--refers to U.S. Pat. No. 4,002,701]; PA1 n=15,2-15 antioxidant [CA 58 14257e (1963)--refers to Fr. Pat. No. 1,309,355; CA 48 1714i (1954)--refers to U.S. Pat. No. 2,654,722]. PA1 64.77% Sugar Solids PA1 34.63% Corn Syrup Solids PA1 0.6% Moisture.